Tuberculosis incidence in foreign-born people residing in European countries in 2020

Background European-specific policies for tuberculosis (TB) elimination require identification of key populations that benefit from TB screening. Aim We aimed to identify groups of foreign-born individuals residing in European countries that benefit most from targeted TB prevention screening. Methods The Tuberculosis Network European Trials group collected, by cross-sectional survey, numbers of foreign-born TB patients residing in European Union (EU) countries, Iceland, Norway, Switzerland and the United Kingdom (UK) in 2020 from the 10 highest ranked countries of origin in terms of TB cases in each country of residence. Tuberculosis incidence rates (IRs) in countries of residence were compared with countries of origin. Results Data on 9,116 foreign-born TB patients in 30 countries of residence were collected. Main countries of origin were Eritrea, India, Pakistan, Morocco, Romania and Somalia. Tuberculosis IRs were highest in patients of Eritrean and Somali origin in Greece and Malta (both > 1,000/100,000) and lowest among Ukrainian patients in Poland (3.6/100,000). They were mainly lower in countries of residence than countries of origin. However, IRs among Eritreans and Somalis in Greece and Malta were five times higher than in Eritrea and Somalia. Similarly, IRs among Eritreans in Germany, the Netherlands and the UK were four times higher than in Eritrea. Conclusions Country of origin TB IR is an insufficient indicator when targeting foreign-born populations for active case finding or TB prevention policies in the countries covered here. Elimination strategies should be informed by regularly collected country-specific data to address rapidly changing epidemiology and associated risks.


Introduction
In the year 1882, when Robert Koch identified a Mycobacterium as the causative agent of tuberculosis (TB), the disease was a common and a leading cause of death in Europe [1].
Migration to European countries, in particular the European Union and the European Economic Area (EU/EEA) accounts for nearly a third of global migration, with 87 million foreign-born individuals living in Europe in 2020 [2].Foreign-born individuals residing in low TB incidence countries have a higher risk of TB than individuals born in these low incidence countries [3].However, reasons for the increased risk of TB in this population are poorly understood and much is still unknown about the epidemiology in this heterogenous group with regard to the routes of migration, incomes, countries of origin, etc.
The incidence of TB in the EU/EEA has steadily declined in the last century [4].Tuberculosis is now a rare disease and a very rare cause of death in most EU/EEA countries [4].According to the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO) Regional office for Europe, the estimated TB incidence rate (IR) in the EU/EEA in 2020 was 9.5 per 100,000 population (95% confidence interval (CI): 9.1-10.0)[4], which was low compared with the global IR of 124 per 100,000 [5].Projections regarding the declining incidence of TB in the EU/EEA suggest that elimination of TB appears to be possible before 2040 [4] as predicted by the WHO END-TB strategy [6].Nevertheless, the decrease in notification rates in native residents is higher than in foreign-born individuals [7].
In 2020, approximately one third of TB cases (10,942/33,148) occurred in foreign-born individuals in the EU/EEA [4].In some EU/EEA countries such as Denmark, Germany, Luxemburg, Norway, the Netherlands and Sweden, more than 60 percent of TB cases occur among foreign-born residents [4].To achieve TB elimination in Europe, it is necessary to timely identify TB among foreign-born individuals [8].
One of the core activities to achieve elimination of TB in countries with low TB incidence is prevention [9], and this relies on active case finding and treatment, vaccination and preventive treatment [10,11].Efforts aimed at eliminating TB should ensure that preventive measures target key populations at risk of TB [8].These measures mainly include active case finding strategies as well as providing TB preventive treatment to exposed individuals (i.e.TB contacts and individuals recently arrived from a high TB incidence country) according to national migrant screening programmes [10].
A programmatic management guideline for latent infection with Mycobacterium tuberculosis (LTBI) by ECDC suggests that people coming from high TB incidence countries should be considered for LTBI screening [12].Interventions should be based on the epidemiological situation of TB in the country of arrival, TB incidence in the country of origin as well as on the travel route, reason for migration and time since leaving the country of origin.However, so far, the relationship between the incidence of TB in the country of origin and the risk of TB in foreign-born individuals in low TB incidence countries in Europe is ill-defined.Further, limited evidence prevents consensus regarding risk assessment and preventive management of TB in foreign-born individuals.
To provide an evidence base for TB detection and prevention policies, we analysed the incidence of TB among foreign-born individuals in EU countries and Iceland, Norway, Switzerland and the UK.We hypothesise that TB incidence rates among foreign-born residents in the EU and Iceland, Norway, Switzerland and the UK reflect TB incidence rates in their countries of origin.

Methods
We conducted a multinational cross-sectional survey among the members of the Tuberculosis Network European Trials group (TBnet) to gather information on foreign-born individuals with TB (some countries, e.g.Germany, provide data on nationality only), indirectly indicating the flow of migrants to the European region.Country representatives from all 27 countries of the European Union as well as Iceland, Norway, Switzerland and the UK were contacted by the study coordinators between May and September 2022 and asked to provide data via a standardised questionnaire.We defined the country of origin as the country where an individual was born and migrated from.We defined the country of residence as the country in which individuals with TB were notified, i.e. the countries participating in our survey.Every country of residence contributed data on (i) the 10 highest ranked countries of origin in terms of number of notified TB cases among foreign-born individuals in the year 2020; (ii) the number of foreignborn individuals with TB from these countries of origin; (iii) the total number of individuals born in these countries of origin and living in the country of residence at the end of the year 2020.
The incidence rate (IR) of TB in foreign-born individuals in the country of residence was calculated by dividing the number of new TB cases notified in the country of residence in 2020 by the number of individuals registered as not born in that country but living there at the end of 2020 (as per 100,000 population).
We considered all foreign-born individuals stemming from one country of origin and living in one country of residence as one population.Foreign-born populations were excluded from the analysis of IR and incidence rate ratio (IRR, see below) if there were fewer than 20 TB cases per country of origin or fewer than 100 foreign-born individuals per country of origin in the dataset.Countries with an IR of less than 100 per 100,000 population were considered countries of low TB burden.
Tuberculosis IRs in the country of residence were compared with WHO-estimated TB IRs and IRs based on notifications in the country of origin as reported by the WHO [5].The incidence rate ratio (IRR) of foreignborn populations was calculated by dividing the IR in the country of residence by the WHO-estimated TB IRs and IRs based on notifications in the country of origin in 2020.
Since in EU countries, as well as Iceland, Norway, Switzerland and the UK, patients with TB are likely being detected, the gap between the number of notified cases and the true number of cases is small and will be substantially smaller than the gap between the number of notified and true incident cases in most countries of origin.
We used a Poisson random effects model to estimate the relative risk (RR) of TB by country of residence and country of origin.We performed spatial analysis using Bayesian inference with integrated Laplace approximation to calculate the mean and standard deviation of the posterior densities per country of residence and country of origin.The 95% credibility interval (CrI) was calculated using the highest posterior densities.
The study protocol was reviewed by independent reviewers and endorsed by the TBnet steering committee.
What did you want to address in this study?One of three patients with tuberculosis (TB) in the European Union/European Economic Area (EU/EEA) is foreign-born.However, there is limited evidence regarding risk assessment, curative and preventive management of TB in foreign-born individuals.We wanted to provide an evidence base for improved TB detection and prevention policies among foreign-born individuals in the EU/EEA.

What have we learnt from this study?
The burden of TB among foreign-born individuals is highly diverse and heterogeneously distributed across Europe.It often reflects historical links.A high TB incidence rate in a person's country of origin is often not aligned with the risk of TB in their country of residence.Thus this should not be the only indicator used to inform guidelines for active case finding and TB prevention in EU/EEA countries.

What are the implications of your findings for public health?
The TB incidence rate in the country of origin is an insufficient indicator when targeting foreign-born populations for active case finding or TB prevention policies in Europe.Tuberculosis elimination strategies should be informed by regularly collected country-specific data to ensure that rapidly changing epidemiology and associated risks are addressed.

KEY PUBLIC HEALTH MESSAGE
Reporting followed the STROBE guidelines [15].

Results
Questionnaires were returned by the end of September 2022 for 30 of 31 countries.Data on foreign-born individuals who developed TB in 2020 in Latvia were not available as they were not recorded.Data on the number of foreign-born individuals living in Belgium, Malta and Romania were only partially available, and as data from 2020 were not available in France, we used the latest available data on the number of foreign-born individuals living in France in 2018.Malta and Greece reported low confidence in their total number of foreign-born individuals from Eritrea and Somalia.The complete dataset is shown in Supplementary Table S1.
For Cyprus, Ireland and Romania there was no clear ranking for the 10th country due to an equivalent number of TB cases.Therefore, more than 10 countries were included in the analysis (Supplementary Table S2).
Country-specific sources of data on the number of foreign-born patients with TB are displayed in Supplementary Table S3.
Data describing 9,116 foreign-born TB cases were gathered via this survey (Table ).These cases stemmed from 75 countries of origin and were recorded in 30 countries of residence, accounting for a total of 267 populations of foreign-born individuals.

Country of residence Country of origin
Countries that appear among the countries of origin and the countries of residence are marked with an asterisk.
The distribution of TB IRs and IRRs in foreign-born populations among countries of residence is shown in Figure 4 for the most common countries of origin of TB cases (alphabetical order): Afghanistan, Eritrea, India, Morocco, Pakistan, Romania, Senegal and Somalia.High tuberculosis IRs (Figure 4A) were observed among populations of Afghani, Eritrean and Somali origin.The population of Afghani origin had a high IR of 337.The figure is sorted according to the WHO incidence with estimation interval according to a WHO report for 2020.
Incidence by country of origin is only reported if there were at least 20 tuberculosis cases and 100 foreign-born individuals in the country of residence.
The TB IRR of people originating from Afghanistan in France was 1.7, i.e. the IR was 1.7-fold higher than in Afghanistan (Figure 4B).

Discussion
In this survey we evaluated TB IRs in foreign-born individuals and compared the relative risk of TB in their country of residence with their country of origin.We identified populations of foreign-born individuals with a high risk of TB, higher than the WHO-estimated risk in their country of origin.To achieve TB elimination in Europe, we conclude that preventative TB strategies must address TB IRs in foreign-born individuals in their country of residence instead of relying on WHOreported TB IRs in their country of origin only.
Overall, most foreign-born TB patients in Europe originated from (in descending order of burden) India, Romania, Morocco, Pakistan, Somalia, Eritrea, Afghanistan, and Senegal.Reasons for the strong representation of these countries of origin among foreignborn individuals with TB are multifactorial but include historical ties, language, pre-existing communities, demand for workers in certain sectors, international trade and/or migration policies [16], but also migration

Figure 3
Incidence rate ratio of tuberculosis in country of residence and incidence rate in country of origin as reported by the WHO based on estimated data, European Union countries and Iceland, Norway, Switzerland and the United Kingdom, 2020 Incidence rate ratios (IRR) presented above the line (Y = 1) have a higher incidence in the country of residence than in country of origin and IRRs presented below the line have a lower incidence in the country of residence than in country of origin.
Incidence rate by country of origin was only reported if there were at least 20 TB cases and 100 foreign-born individuals in the country of residence.

Figure 4
Tuberculosis incidence, European Union, Iceland, Norway, Switzerland and United Kingdom, 2020 a Observed and WHO-estimated TB incidence rate (IR) in foreign-born individuals.
b Tuberculosis IR among foreign-born residents in their country of residence divided by the WHO-estimated TB IR in their country of origin using 2020 data.
Incidence rate is reported per 100,000 population.
Incidence rate by country of origin was only reported if there were at least 20 TB cases and 100 foreign-born individuals in the country of residence.
The figure has been produced with datawrapper.dedue to socioeconomic situation, civil unrest/war, climate change and natural disasters.These patterns become evident and are highlighted by migrant flows between countries of origin and countries of residence.
There was substantial heterogeneity in TB IRs among foreign-born individuals throughout the surveyed countries.In many European countries of residence we observed high TB IRs in people from Afghanistan, Eritrea and Somalia, areas with war or conflict situations that facilitate the spread and hamper the prevention and control of TB.However, we also observed high IRs in specific populations such as people from Mozambique residing in Portugal.Previous research has shown that migration from outside the EU/EEA contributes markedly to the TB burden in the EU/EEA [17].
For almost 80% of the populations included in this dataset, the TB IR in the country of residence was not aligned with the WHO-estimated IR in the country of origin.In fact, 60% of populations had an IR below the WHO-estimated IR in the country of origin and 20% had a higher IR than estimated by the WHO for their country of origin.
Possible explanations for lower TB IRs in countries of residence could be lower risk of TB transmission in the country of residence, higher socioeconomic status of the migrants, long time passed since migration [18,19] and a long time since exposure to TB [20].Effective past screening policies, for example systematic X-ray screening, might also contribute to decreased incidence today.Low TB IRs in Somalian populations in Sweden illustrate this phenomenon.It results from a combination of factors, including longer residency in Sweden for the majority of Somalian individuals and the implementation of effective policies.These policies encompass free TB and latent TB testing for all asylum seekers arriving from Somalia, as well as the administration of BCG vaccinations to children in families with ties to Somalia.These measures have been in place since 2008, with minor modifications in various years and provinces, as stipulated by the Swedish law (SFS nr: 2008:344) [21].
Possible explanations for higher TB IRs in countries of residence are routes of migration that are associated with a higher risk of transmission (e.g.residing in overcrowded refugee camps or travelling in crowded vehicles) as well as post-migration transmission (e.g.residing in refugee centres), short time since exposure or arrival, effective TB screening policies, lower socioeconomic status in their country of origin and a population structure that mostly consist of young men.High IRs in, Afghani, Eritrean and Somalian populations in Malta and/or Greece may be examples of these factors.
People of Eritrean and Somalian origin accounted for more than half of the populations with higher TB IRs in the country of residence than the country of origin.
Additionally, for Eritrea in particular, the WHO estimates of 81 cases per 100,000 population are likely underestimated.
The RR of being notified with TB in a country of residence was highest in Malta.This could relate to a high number of migrants arriving in this country, sometimes temporarily.Malta often represents the first contact of non-European populations with the European health system.Generally, there is an increased risk of TB exposure or disease activation during migration, in addition to the risk of abuse, human rights violations [22,23].Moreover, foreign-born individuals often seek care only at an advanced stage of TB disease [3] and there can be considerable delay in accessing diagnostic services [24].
Our results suggest that the TB IR in the country of origin should not be the only indicator when deciding on active case finding or TB prevention policies for foreign-born populations [25].Introducing a universal screening threshold for foreign-born individuals based on the TB IR in the country of origin, e.g. at an estimated incidence rate of 100 per 100,000 population in the country of origin, may not be an effective screening method for all European countries.A study conducted in Germany found that the difference in observed yield of TB screening among asylum seekers from different countries of origin decreased gradually when higher cut-offs of WHO-estimated TB IRs were used [26].In contrast with screening depending on a specific TB incidence in the country of origin, future strategies for TB prevention and early case finding on the path towards TB elimination should be guided by regularly collected country-specific data on populations at risk of developing TB.
Our study has several limitations.Given that individual patient data including age and year of arrival were not available in our data sources, it was not possible to investigate links with population characteristics.Data on age and sex would have been available through the ECDC European Surveillance System (TESSy) database.However, data on the time of incident TB after arrival to the respective country in the EU/EEA are not.Future prospective studies would benefit from including individual patient data to inform screening policies.We only considered notified foreign-born TB patients and only the total number of documented foreign-born individuals in a country of residence.Some TB patients included in our data could be among undocumented foreign-born individuals.Moreover, TB patients may remain undetected and 5-30% of foreign-born migrants may not be documented in their country of residence [27].It is suggested that the burden of tuberculosis may be 10% higher in undocumented migrants [22,27], while others may have moved and may have been notified in two or more countries in 2020.There was also substantial variation in the country of origin TB IRs based on estimated numbers or notified numbers of cases, reflecting variations in the TB detection gap.
Factors that partly drive TB IRs, i.e. risk of transmission during and post migration, time since exposure and/or arrival, tuberculosis-screening policies in the country of residence, socioeconomic status in the country of origin and the reason for migration as well as demographic factors such as age and sex were not available for most surveyed countries.Tuberculosis reactivation rates post-migration are likely dependent on both time from exposure/migration and age [18,20].Moreover, different European countries' screening policies certainly impact TB detection and prevention.During the period 2011-2022, the annual average decline in TB IRs in the EU/EAA was 5.2%, with 6.2% achieved between 2019 and 2020 [4].While it can be assumed that the observed decrease in TB incidence between 2019 and 2020 was partly affected by a decrease in migration to the EU/EEA and decreased TB notifications due to COVID-19 restrictions in 2020 [5], our data are highly relevant to inform TB control strategies for the next decade.We only considered data from the 10 countries of origin with the highest number of foreignborn TB cases in each country of residence to find a balance between a broad representation of all countries in the region and the aim to capture foreign-born individuals at highest risk for TB in European countries of residence.This approach may have led to underrepresentation of foreign-born individuals from countries with a lower number of TB cases in the included countries.Finally, we primarily based our analysis on estimated IRs in countries of origin as reported to the WHO because these data are predominantly available to policymakers.It is possible that for some countries, e.g.Eritrea, where the incidence estimates are low for the region while incidence is high in Eritrean migrants, WHO estimates of TB IRs are inaccurate, leading to incorrect guidance for TB screening.
Despite these limitations, our research using comprehensive latest available data from countries in the European Union and Iceland, Norway, Switzerland and the UK supports national solutions based on recent risk analyses to target TB prevention and case finding strategies among foreign-born individuals.Social determinants of health are known to be strong risk factors for progression towards active TB.Interventions aimed at improving socioeconomic conditions in foreign-born populations could prevent new TB cases.

Conclusion
The burden of TB among foreign-born individuals is highly diverse and heterogeneously distributed across Europe.A high TB IR in the country of origin is often not aligned with the risk of TB in foreign-born populations living in Europe.Therefore, this should not be the only indicator used to inform guidelines for active case finding and TB prevention in EU countries and Iceland, Norway, Switzerland and the UK.Curative and preventative TB control and elimination strategies should be informed by regularly collected country-specific data to ensure that changing epidemiology and associated risks are addressed.

Ethical statement
This study did not require ethical board approval as no individual patient data were evaluated.
z e g o v i n a S y r i a T ü r k i y e P o l a n d WHO: World Health Organization.Each dot represents incidence in foreign-born residents from one country of origin in one country of residence.Box: interquartile range.Whiskers: min and max.Each square represents the estimated tuberculosis incidence in a country of origin for 2020.Error bars represent the uncertainty intervals.

E
incidence of tuberculosis in country of residence and reported incidence in country of origin g a s c a r A l g e r i a B a n g l a d e s h V i e t n a m U k r a i n e N i g e r i a I n d o n e s i a P h i l i p p i n e sCountry of residenceUncertainty interval of the WHO estimateEvery dot represents one country of residence.Sorted by median ratio.Boxes: interquartile range (IQR), whiskers: min and max.

Table
Number of tuberculosis cases among foreign-born residents and total number of foreign-born residents from the 10 highest ranked countries of origin in terms of the highest tuberculosis burden, European Union countries and Iceland, Norway, Switzerland and the United Kingdom, 2020 the UK were often from Bangladesh, India or Pakistan.Similarly, the main migration pattern of TB cases from Bolivia, Colombia, Ecuador and Venezuela was towards Spain, and TB cases from Angola, Cabo Verde and Mozambique were mostly identified in Portugal.Countries of origin of foreign-born tuberculosis cases residing in European Union countries and Iceland, Norway, Switzerland and the United Kingdom, 2020 IR: incidence rate; NA: not available; TB: tuberculosis; WHO: World Health Organization.a From the 10 highest ranked countries of origin in terms of number of notified TB cases among foreign-born individuals in the year 2020.b Incidence rate is reported per 100,000 population in the year 2020. in our sample: India (14.7%),Pakistan (9.7%), Romania (9.3%), Morocco (8.9%), Somalia (7.2%), Eritrea (6.3%), Afghanistan (4.5%) and Senegal (3.7%).All other countries accounted for less than 5% of all foreign-born TB cases and less than 500 cases each.In some countries of residence, we highlight specific migratory patterns within their top 10 countries of origin: foreign-born TB cases in (observed IR: 110.5/100,000,WHO estimated IR: 98.0/100,000); (ii) people of Malian origin living in France (166/90,537) (observed IR: 183.4/100,000,WHO estimated IR: 52.0/100,000); (iii) people from Cabo Verde living in Portugal (41/36,609) (observed IR: 112/100,000, WHO estimated IR: 39.0/100,000).Tuberculosis IR in individuals of Eritrean origin (WHO estimated IR: 81/100,000) was higher than 100 per 100,000 population in all countries of residence except for Norway and Sweden (see below).For 48 populations (56.5%) from 25 countries of origin, TB IR in the country of residence was below the WHO estimate.The TB IR was below the WHO estimates for all observed populations for 23 of 37 countries of origin.IRR was highest in populations of Eritrean and Somali origin in Malta and of Somali origin in Greece (IRR > 5), followed by people of Eritrean origin in the Figure 1 Observed incidence rate of tuberculosis per 100,000 foreign-born individuals per country of residence vs incidence in their country of origin as reported by the WHO based on estimated data, European Union countries and Iceland, Norway, Switzerland and the United Kingdom, 2020 5 per 100,000 in France, 254.0 per 100,000 in Belgium and 224.8 per 100,000 in Greece, while there was a notably lower IR in the UK (119.1/100,000),Germany